The focus of this project is the use of MRI to understand the pathophysiology of multiple sclerosis (MS) and to determine whether disease activity is altered by various immunomodulatory treatments such as Anti-Tac antibodies (Zenapex) or Roliprom, a phosphodiesterase 4 inhibitor and to monitor the natural history of MS, Anti-Tac antibodies in combination with Interferon beta have resulted in improvement of clinical and MRI MS disease activity in patients that were previously considered non-responders to conventional therapy. Studies are now underway to see if Zenapex alone can be used as front line therapy in MS. A phase II trial is underway evaluating the new oral agent, Roliprom for the treatment of relapsing remitting MS patients using suppression of frequency of enhancing lesions as an outcome measure. Enrollment has started of active early relapsing remitting MS patients into this study and changes in enhancing lesions compared to baseline disease activity will be used as primary outcome measure. T1- black holes (BHs) on MRI represent either areas of edema, axonal loss or astrogliosis and correlate with disability in patients with MS. We investigated the heterogeneity of BHs? appearance over 48 consecutive months in relapsing remitting MS patients, the role of contrast enhancing lesions (CEL) on BHs? formation, (iii) the role of CEL duration on BHs? duration over time and observed that formation of BHs is related to the amount of CEL. However the duration of BH once those lesions have been formed is most likely a consequence of the duration of the enhancement and blood brain barrier disruption. This new observation on persistent BH overtime indicated that it is possible that axonal loss and gliotic scars can resolve on MRI about 21 months following their initial appearance coinciding with an acute inflammatory lesion. Recently, new vessel proliferation and formation (angiogenesis) has been observed in autopsy and biopsy specimens from patients with multiple sclerosis (MS). In the newly formed MS lesions, there was striking increased numbers of new vessels and similar patterns were observed in and around older lesions, areas of remyelination (i.e., new myelin formation on axons, shadow plaques) and normal appearing brain tissue. Experimental and clinical studies are being performed to quantify regional cerebral blood flow (CBF) comparing CBF of MS patients, to age and gender-matched healthy controls using perfusion MRI techniques. In addition patients will undergo a 6% carbon dioxide (hypercapnia) inhalation challenge to determine if vascular responsiveness in MS patients is similar to healthy controls. Comparing the CBF response to hypercapnia will determine if the newly formed vasculature includes properly functioning blood vessels. Normal cerebral blood vessels are exquisitely sensitive to the carbon dioxide in arterial blood and an increase in carbon dioxide causes CBF to increase through dilatation or relaxation of the muscles surrounding the blood vessels. In the future, changes in the hypercapnia-induced CBF response between MS patients and controls may help to monitor the treatment of the disease.